Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial

• Published in: JAMA : the journal of the American Medical Association 2001-10, Vol.286 (15), p.1869
• Main Authors: Warren, B L, Eid, A, Singer, P, Pillay, S S, Carl, P, Novak, I, Chalupa, P, Atherstone, A, Pénzes, I, Kübler, A, Knaub, S, Keinecke, H O, Heinrichs, H, Schindel, F, Juers, M, Bone, R C, Opal, S M
• Format: Article
• Language: English
• Subjects: Adult; Anticoagulants - administration & dosage; Anticoagulants - therapeutic use; Antithrombin III - administration & dosage; Antithrombin III - therapeutic use; Double-Blind Method; Drug Interactions; Female; Heparin - therapeutic use; Humans; Male; Multiple Organ Failure - etiology; Multiple Organ Failure - prevention & control; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - therapeutic use; Shock, Septic - complications; Shock, Septic - drug therapy; Survival Analysis; Systemic Inflammatory Response Syndrome - complications; Systemic Inflammatory Response Syndrome - drug therapy; Thrombosis - etiology; Thrombosis - prevention & control
• ISSN: 0098-7484

Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients. To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock. Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000. A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin). All-cause mortality 28 days after initiation of study medication. Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P